The International Consortium on the Genetics of Lupus (SLEGEN) published a genome wide association study (GWAS) with multiple replications of the major associations with Systemic Lupus Erythematosus (SLE) (Nat Gen 40:204, 2008), identifying 18 genetic effects, 13 of which were not previously described. This study was confined to European-ancestry women and we know that there are major differences between ancestral groups with regard to lupus susceptibility. For example, the Hispanics studied to date do not have a strong HLA association, which in European-ancestry women is the strongest association (OR=2.36, p<10E-50). We propose to use the resources of this RFA-CA-09-003 "Replication and Fine-Mapping Studies for the Genes Environment and Health Initiative (GEI)" to replicate candidate associations from the GWAS and other studies in Amerindian admixed Hispanics by testing 38,000 bead types (about 33,000 markers) in 3440 Amerindian admixed Hispanics, half cases and half controls. We will maximize the Amerindian component selecting populations that have high Amerindian content and low African ancestry. Data cleaning and stratification correction will follow our previous experience and exploit recent advances (e.g., random projection). These Amerindian admixed Hispanics will make possible completing an experiment underway with 38,000 bead types in 14,000 subjects (lupus cases and controls) of European, African-American, and East Asian ancestry (funded from other sources). This will make trans-ancestry mapping of genetic effects possible. Trios and additional Amerindian admixed Hispanic case and control materials are available for additional replication, fine mapping, and sequencing, which will be organized subsequently, beyond the funding requested herein. We expect to identify genes important for Amerindian admixed Hispanics, to identify whether the risk alleles are from European or Native American genomes, and to use subjects from other ancestral origins to further restrict their genomic location. These genes are important in lupus pathogenesis and their discovery and character will spawn new diagnostic and therapeutic approaches to this deadly disorder.